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Fulltext Detection of malachite green and leuco-malachite green in fishery industry

Hidayah, N., Abu Bakar, F., Mahyudin, N.A., Faridah, S., Nur-Azura, M.S., Zaman, M.Z.

International Food Research Journal, 2013;20(4):1511-1519.
MyJurnal

This article summarises the current methods for total malachite green (MG) detection which is known as a sum of MG and leuco-malachite green (LMG) that has been used extensively in aquaculture as fungicide, dye color in textile and other purposes in food industries. LMG is a reducing form of MG, where the MG is easily reduced due to the photo-oxidative de-methylation process. Nevertheless, the use of MG had become an issue due to its toxicity effects. Many analytical instruments such as HPLC, LC—MS/MS, GC—MS, and spectrometry have been widely used for detection of MG. However, these methods require long time sample preparation and analysis, expensive, use hazardous reagents and indirect measurements. Hence, other analytical methods which are more sensitive, safe, rapid, inexpensive and portable are required. Alternatively, biosensors promise a more sensitive and rapid detection method for MG and LMG.

Matched MeSH terms: Methylation
Fulltext Pyrosequencing-based quantitative evaluation of P16 methylation in diffuse large b-cell lymphoma

Mohd. Ridah L.J., Ismail A., A. Talib N., Muhammad N., Hussain F.A., Zainuddin N.

Journal of Biomedical and Clinical Sciences, 2016;1(1):12-17.
MyJurnal

Introduction: Methylation of promoter region of p16 leading to gene silencing has been implicated ina wide range of malignancies including lymphomas. In diffuse large B cell lymphoma (DLBCL) particularly, a varying percentage of epigenetic inactivation of p16 promoter region was observed ranging from 16 -54%. However, quantitative analysis of p16 promoter methylation in DLBCL has not been extensively studied in Malaysia. Objective: This study aims to quantitatively analyse p16 methylation in DLBCL samples using pyrosequencing technique. Methods: Genomic DNA was extracted from 16 formalin-fixed paraffin-embedded lymphoma tissue blocks from patients diagnosed with DLBCL. Samples were retrieved from Hospital Tengku Ampuan Afzan, Pahang and Hospital Universiti Sains Malaysia, Kelantan. Primers were designed to amplify bisulfite-treated DNA targeting p16 promoter region. Methylation status of 7 CpG sites was determined by pyrosequencing. Results: All the 16 samples studied showed promoter methylation of p16. The range of mean methylation percentage was between 18 to 81%. Conclusion: The present study has successfully measured the level of methylation of p16 in all 7 CpG sites despite the limitation in sample size. Since p16 methylation is a common event in our series of DLBCL cases, it is worth including a larger sample size in future studies to increase the chance of finding a significant correlation with clinical parameters.

Matched MeSH terms: Methylation
Fulltext MGMT and SPOCK2 Promoter Methylation in diffuse large B-Cell Lymphoma: a study in two tertiary health centres in the East Coast of Malaysia

Norafiza Zainuddin, Lailatul Jalilah Mohd Ridah, Aqilah Nabihah Omar, Norlelawati A. Talib, Naznin Muhammad, Faezahtul Arbaeyah Hussain

Jurnal Sains Kesihatan Malaysia, 2017;15(2):77-82.
MyJurnal

MGMT (O6
-Methylguanine-DNA Methyltransferase) suppresses tumor development by removing alkyl adduct, while
SPOCK2 (SPARC/Osteonectin CWCV and Kazal-like domains proteoglycan) abolishes the inhibition of membrane-type
matrix metalloproteinases (MT-MMP) which leads to angiogenesis. Hence, MGMT methylation may initiate malignant cells
transformation. In contrast, SPOCK2 methylation is hypothesized not to be a common event in diffuse large B-cell lymphoma
(DLBCL). In this study, we examined the methylation status of MGMT and SPOCK2 in DLBCL as in Malaysia the information
is extremely lacking. A total of 88 formalin-fixed paraffin-embedded tissue of patients diagnosed with DLBCL from the
year 2006 to 2013 were retrieved from Hospital Universiti Sains Malaysia, Kelantan and Hospital Tengku Ampuan Afzan,
Pahang. Methylation-specific polymerase chain reaction (MSP) was used to examine the methylation status of both genes.
Interestingly, methylation of MGMT was detected in all the 88 DLBCL samples, whereas SPOCK2 was found to be methylated
in 83 of 88 (94.3%) DLBCL cases. Our study showed a remarkably high percentage of promoter methylation of both
MGMT and SPOCK2 genes. Our finding also negates initial expectation that SPOCK2 methylation would be an uncommon
event in the majority of DLBCL cases. This study has shown a very high percentage of promoter methylation of MGMT and
SPOCK2 in the DLBCL cases studied by MSP, using archival lymphoma tissues. Nonetheless, additional research is needed
to quantitatively evaluate MGMT and SPOCK2 methylation, and to analyse gene expression and/or protein expression in
order to further understand the role of MGMT and SPOCK2 methylation in the pathogenesis of DLBCL.

Matched MeSH terms: Methylation
Fulltext Azacytidine enhances sensitivity response to imatinib in BCR/ABL positive CML cell line

Hamid Ali Nagi Al-Jamal, Wan Rohani Wan Taib, Siti Asmaa Mat Jusoh, Aziee Sudin, Muhammad Farid Johan

Journal of Biomedical and Clinical Sciences, 2017;2(202):20-22.
MyJurnal

Azacytidine (5-Aza) is a chemotherapeutic drug that has been known to restore the expression of Tumour suppressor genes by de-methylation and shown clinical efficacy inMyelodysplastic syndrome (MDS) [1-3]. Currently, 5-Aza is being used in UK for the treatment of some adults with MDS, chronic myelocytic leukemia (CML) and acute myelocytic leukemia (AML) [4]. Majority of CML patients treated with imatinib, a BCR/ABL inhibitor would develop resistance under prolonged therapy. Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that is constitutively activated in various human cancers including hematological malignancies. Activation of STAT3 represents an important mechanism of imatinib resistant [5]. Methylation of SHP-1is involved in the constitutive activation of STAT3 [6], and a low level of SHP-1is not sufficient to inhibit activated STAT3 [7]. Epigenetic silencing of SHP-1also plays a role in the development of resistance to imatinib in BCR/ABL positive CML cells.

Matched MeSH terms: Methylation
Epigenetics in Metastatic Breast Cancer: Its Regulation and Implications in Diagnosis, Prognosis and Therapeutics

Wu YS, Lee ZY, Chuah LH, Mai CW, Ngai SC

Curr Cancer Drug Targets, 2019;19(2):82-100.
PMID: 29714144 DOI: 10.2174/1568009618666180430130248

Despite advances in the treatment regimen, the high incidence rate of breast cancer (BC) deaths is mostly caused by metastasis. Recently, the aberrant epigenetic modifications, which involve DNA methylation, histone modifications and microRNA (miRNA) regulations become attractive targets to treat metastatic breast cancer (MBC). In this review, the epigenetic alterations of DNA methylation, histone modifications and miRNA regulations in regulating MBC are discussed. The preclinical and clinical trials of epigenetic drugs such as the inhibitor of DNA methyltransferase (DNMTi) and the inhibitor of histone deacetylase (HDACi), as a single or combined regimen with other epigenetic drug or standard chemotherapy drug to treat MBCs are discussed. The combined regimen of epigenetic drugs or with standard chemotherapy drugs enhance the therapeutic effect against MBC. Evidences that epigenetic changes could have implications in diagnosis, prognosis and therapeutics for MBC are also presented. Several genes have been identified as potential epigenetic biomarkers for diagnosis and prognosis, as well as therapeutic targets for MBC. Endeavors in clinical trials of epigenetic drugs against MBC should be continued although limited success has been achieved. Future discovery of epigenetic drugs from natural resources would be an attractive natural treatment regimen for MBC. Further research is warranted in translating research into clinical practice with the ultimate goal of treating MBC by epigenetic therapy in the near future.

Matched MeSH terms: DNA Methylation
Fulltext Mechanism of biosorption of Pb (ii) and Cu (ii) ions using dead biomass of Fusarium equiseti strain UMAS and Penicillium citrinum strain UMAS B2

Wahab Abideen Akinkunmi, Awang Ahmad Sallehin Awang Husaini, Azham Zulkharnain, Tay, Meng Guan, Hairul Azman Roslan

Journal of Biochemistry, Microbiology and Biotechnology, 2016;4(2):1-6.
MyJurnal

Filamentous fungi such as Fusarium equiseti KR706303 and Penicillium citrinum KR706304
are capable of sequestering heavy metals from aqueous solutions. In the present study, the role
play by various functional groups present in the cell wall of F. equiseti KR706303 and P.
citrinum KR706304 during lead and copper ions biosorption was investigated. The fungal
biomass was chemically treated to modify the functional groups present in their cell wall. These
modifications were studied through biosorption experiments. It was found that an esterification
of the carboxyl and phosphate groups, methylation of the amine groups and extraction of lipids
significantly decrease the biosorption of both lead and copper ions studied. Therefore, the
carbonyl, hydroxyl and amide groups were recognized as important in the biosorption of metal
ions by the tested fungi. The study showed that there was no release of any metal ions from the
biomass after biosorption, indicating that ion exchange may not be a key mechanism in the
biosorption of lead and copper ions by these fungi but complexation of metal ions within the
fungal cell wall.

Matched MeSH terms: Methylation
Synthesis, X-ray crystal and monoamine oxidase inhibitory activity of 4,6-dihydrobenzo[c]pyrano[2,3-e][1,2]thiazine 5,5-dioxides: In vitro studies and docking analysis

Ahmad S, Jalil S, Zaib S, Aslam S, Ahmad M, Rasul A, et al.

Eur J Pharm Sci, 2019 Apr 01;131:9-22.
PMID: 30735822 DOI: 10.1016/j.ejps.2019.02.007

We report the synthesis and biological evaluation of two new series of 2-amino-6-benzyl-4-phenyl-4,6-dihydrobenzo[c]pyrano[2,3-e][1,2]thiazine-3‑carbonitrile 5,5-dioxides and 2-amino-6-methyl-4-phenyl-4,6-dihydrobenzo[c]pyrano[2,3-e][1,2]thiazine-3‑carbonitrile 5,5-dioxides. The synthetic methodology involves a multistep reaction starting with methyl anthranilate which was coupled with methane sulfonyl chloride. The product of the reaction was subjected to N-benzylation and N-methylation reactions followed by ring closure with sodium hydride resulting in the formation of respective 2,1-benzothiazine 2,2-dioxides. These 2,1-benzothiazine precursors were subjected to multicomponent reaction with malononitrile and substituted benzaldehydes for the synthesis of two new series of pyranobenzothiazines (6a-r and 7a-r). The synthesized compounds were screened as selective inhibitors of monoamine oxidase A and monoamine oxidase B. The in vitro results suggested that compound 6d and 7q are the selective inhibitors of monoamine oxidase A, however, the selective and potent inhibitors of monoamine oxidase B included compounds 6h and 7r. Moreover, some dual inhibitors were noticed like 7l having more inhibitory activity towards both the isozymes. Moreover, the binding modes of the selective and potent inhibitors of monoamine oxidase A and B were investigated by molecular docking analysis. The results suggested that the synthetic derivatives may be potential towards the monoamine oxidase isozymes.

Matched MeSH terms: Methylation
Fulltext Differential Analysis of Genetic, Epigenetic, and Cytogenetic Abnormalities in AML

Islam M, Mohamed Z, Assenov Y

Int J Genomics, 2017;2017:2913648.
PMID: 28713819 DOI: 10.1155/2017/2913648

Acute myeloid leukemia (AML) is a haematological malignancy characterized by the excessive proliferation of immature myeloid cells coupled with impaired differentiation. Many AML cases have been reported without any known cytogenetic abnormalities and carry no mutation in known AML-associated driver genes. In this study, 200 AML cases were selected from a publicly available cohort and differentially analyzed for genetic, epigenetic, and cytogenetic abnormalities. Three genes (FLT3, DNMT3A, and NPMc) are found to be predominantly mutated. We identified several aberrations to be associated with genome-wide methylation changes. These include Del (5q), T (15; 17), and NPMc mutations. Four aberrations-Del (5q), T (15; 17), T (9; 22), and T (9; 11)-are significantly associated with patient survival. Del (5q)-positive patients have an average survival of less than 1 year, whereas T (15; 17)-positive patients have a significantly better prognosis. Combining the methylation and mutation data reveals three distinct patient groups and four clusters of genes. We speculate that combined signatures have the better potential to be used for subclassification of AML, complementing cytogenetic signatures. A larger sample cohort and further investigation of the effects observed in this study are required to enable the clinical application of our patient classification aided by DNA methylation.

Matched MeSH terms: DNA Methylation
Hepatitis B virus DNA methylation and its potential role in chronic hepatitis B

Low WF, Ngeow YF, Chook JB, Tee KK, Ong SK, Peh SC, et al.

Expert Rev Mol Med, 2022 Nov 16;25:e11.
PMID: 36380484 DOI: 10.1017/erm.2022.38

Hepatitis B virus (HBV) infection led to 66% liver deaths world-wide in year 2015. Thirty-seven per cent of these deaths were the result of chronic hepatitis B (CHB)-associated hepatocellular carcinoma (HCC). Although early diagnosis of HCC improves survival, early detection is rare. Methylation of HBV DNA including covalently closed circular DNA (cccDNA) is more often encountered in HCC cases than those in CHB and cirrhosis. Three typical CpG islands within the HBV genome are the common sites for methylation. The HBV cccDNA methylation affects the viral replication and protein expression in the course of infection and may associate with the disease pathogenesis and HCC development. We review the current findings in HBV DNA methylation that provide insights into its role in HCC diagnosis.

Matched MeSH terms: DNA Methylation
Fulltext Comparison of two derivatization methods for the analysis of fatty acids and trans fatty acids in bakery products using gas chromatography

Salimon J, Omar TA, Salih N

ScientificWorldJournal, 2014;2014:906407.
PMID: 24719581 DOI: 10.1155/2014/906407

Two different procedures for the methylation of fatty acids (FAs) and trans fatty acids (TFAs) in food fats were compared using gas chromatography (GC-FID). The base-catalyzed followed by an acid-catalyzed method (KOCH3/HCl) and the base-catalyzed followed by (trimethylsilyl)diazomethane (TMS-DM) method were used to prepare FA methyl esters (FAMEs) from lipids extracted from food products. In general, both methods were suitable for the determination of cis/trans FAs. The correlation coefficients (r) between the methods were relatively small (ranging from 0.86 to 0.99) and had a high level of agreement for the most abundant FAs. The significant differences (P = 0.05) can be observed for unsaturated FAs (UFAs), specifically for TFAs. The results from the KOCH3/HCl method showed the lowest recovery values (%R) and higher variation (from 84% to 112%), especially for UFAs. The TMS-DM method had higher R values, less variation (from 90% to 106%), and more balance between variation and %RSD values in intraday and interday measurements (less than 4% and 6%, resp.) than the KOCH3/HCl method, except for C12:0, C14:0, and C18:0. Nevertheless, the KOCH3/HCl method required shorter time and was less expensive than the TMS-DM method which is more convenient for an accurate and thorough analysis of rich cis/trans UFA samples.

Matched MeSH terms: Methylation
Screening of differential promoter hypermethylated genes in primary oral squamous cell carcinoma

Khor GH, Froemming GR, Zain RB, Abraham MT, Thong KL

Asian Pac J Cancer Prev, 2014;15(20):8957-61.
PMID: 25374236

BACKGROUND: Promoter hypermethylation leads to altered gene functions and may result in malignant cellular transformation. Thus, identification of biomarkers for hypermethylated genes could be useful for diagnosis, prognosis, and therapeutic treatment of oral squamous cell carcinoma (OSCC).
OBJECTIVES: To screen hypermethylated genes with a microarray approach and to validate selected hypermethylated genes with the methylation-specific polymerase chain reaction (MSPCR).
MATERIALS AND METHODS: Genome-wide analysis of normal oral mucosa and OSCC tissues was conducted using the Illumina methylation microarray. The specified differential genes were selected and hypermethylation status was further verified with an independent cohort sample of OSCC samples. Candidate genes were screened using microarray assay and run by MSPCR analysis.
RESULTS: TP73, PIK3R5, and CELSR3 demonstrated high percentages of differential hypermethylation status.
CONCLUSIONS: Our microarray screening and MSPCR approaches revealed that the signature candidates of differentially hypermethylated genes may possibly become potential biomarkers which would be useful for diagnostic, prognostic and therapeutic targets of OSCC in the near future.

Matched MeSH terms: DNA Methylation*
Methylation of the filaggrin gene promoter does not affect gene expression and allergy

Tan HT, Ellis JA, Koplin JJ, Martino D, Dang TD, Suaini N, et al.

Pediatr Allergy Immunol, 2014 Oct;25(6):608-10.
PMID: 24912553 DOI: 10.1111/pai.12245
Matched MeSH terms: DNA Methylation*
Fulltext Analyses of hypomethylated oil palm gene space

Low ET, Rosli R, Jayanthi N, Mohd-Amin AH, Azizi N, Chan KL, et al.

PLoS One, 2014;9(1):e86728.
PMID: 24497974 DOI: 10.1371/journal.pone.0086728

Demand for palm oil has been increasing by an average of ∼8% the past decade and currently accounts for about 59% of the world's vegetable oil market. This drives the need to increase palm oil production. Nevertheless, due to the increasing need for sustainable production, it is imperative to increase productivity rather than the area cultivated. Studies on the oil palm genome are essential to help identify genes or markers that are associated with important processes or traits, such as flowering, yield and disease resistance. To achieve this, 294,115 and 150,744 sequences from the hypomethylated or gene-rich regions of Elaeis guineensis and E. oleifera genome were sequenced and assembled into contigs. An additional 16,427 shot-gun sequences and 176 bacterial artificial chromosomes (BAC) were also generated to check the quality of libraries constructed. Comparison of these sequences revealed that although the methylation-filtered libraries were sequenced at low coverage, they still tagged at least 66% of the RefSeq supported genes in the BAC and had a filtration power of at least 2.0. A total 33,752 microsatellites and 40,820 high-quality single nucleotide polymorphism (SNP) markers were identified. These represent the most comprehensive collection of microsatellites and SNPs to date and would be an important resource for genetic mapping and association studies. The gene models predicted from the assembled contigs were mined for genes of interest, and 242, 65 and 14 oil palm transcription factors, resistance genes and miRNAs were identified respectively. Examples of the transcriptional factors tagged include those associated with floral development and tissue culture, such as homeodomain proteins, MADS, Squamosa and Apetala2. The E. guineensis and E. oleifera hypomethylated sequences provide an important resource to understand the molecular mechanisms associated with important agronomic traits in oil palm.

Matched MeSH terms: DNA Methylation*
Involvement of CELSR3 Hypermethylation in Primary Oral Squamous Cell Carcinoma

Khor GH, Froemming GR, Zain RB, Abraham TM, Lin TK

Asian Pac J Cancer Prev, 2016;17(1):219-23.
PMID: 26838213

BACKGROUND: Promoter hypermethylation is a frequent epigenetic mechanism for gene transcription repression in cancer and is one of the hallmarks of the disease. Cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) contributes to cell contact-mediated communication. Dysregulation of promoter methylation has been reported in various cancers.
OBJECTIVES: The objectives of this study were to investigate the CELSR3 hypermethylation level in oral squamous cell carcinomas (OSCCs) using methylation-sensitive high-resolution melting analysis (MS-HRM) and to correlate CELSR3 methylation with patient demographic and clinicopathological parameters.
MATERIALS AND METHODS: Frozen tissue samples of healthy subjects' normal mucosa and OSCCs were examined with regard to their methylation levels of the CELSR3 gene using MS-HRM.
RESULTS: MS-HRM analysis revealed a high methylation level of CELSR3 in 86% of OSCC cases. Significant correlations were found between CELSR3 quantitative methylation levels with patient ethnicity (P=0.005), age (P=0.024) and pathological stages (P=0.004). A moderate positive correlation between CELSR3 and patient age was also evident (R=0.444, P=0.001).
CONCLUSIONS: CELSR3 promoter hypermethylation may be an important mechanism involved in oral carcinogenesis. It may thus be used as a biomarker in OSCC prognostication.

Matched MeSH terms: DNA Methylation/genetics*
Exploring breast carcinogenesis through integrative genomics and epigenomics analyses

Minning C, Mokhtar NM, Abdullah N, Muhammad R, Emran NA, Ali SA, et al.

Int J Oncol, 2014 Nov;45(5):1959-68.
PMID: 25175708 DOI: 10.3892/ijo.2014.2625

There have been many DNA methylation studies on breast cancer which showed various methylation patterns involving tumour suppressor genes and oncogenes but only a few of those studies link the methylation data with gene expression. More data are required especially from the Asian region and to analyse how the epigenome data correlate with the transcriptome. DNA methylation profiling was carried out on 76 fresh frozen primary breast tumour tissues and 25 adjacent non-cancerous breast tissues using the Illumina Infinium(®) HumanMethylation27 BeadChip. Validation of methylation results was performed on 7 genes using either MS-MLPA or MS-qPCR. Gene expression profiling was done on 15 breast tumours and 5 adjacent non-cancerous breast tissues using the Affymetrix GeneChip(®) Human Gene 1.0 ST array. The overlapping genes between DNA methylation and gene expression datasets were further mapped to the KEGG database to identify the molecular pathways that linked these genes together. Supervised hierarchical cluster analysis revealed 1,389 hypermethylated CpG sites and 22 hypomethylated CpG sites in cancer compared to the normal samples. Gene expression microarray analysis using a fold-change of at least 1.5 and a false discovery rate (FDR) at p>0.05 identified 404 upregulated and 463 downregulated genes in cancer samples. Integration of both datasets identified 51 genes with hypermethylation with low expression (negative association) and 13 genes with hypermethylation with high expression (positive association). Most of the overlapping genes belong to the focal adhesion and extracellular matrix-receptor interaction that play important roles in breast carcinogenesis. The present study displayed the value of using multiple datasets in the same set of tissues and how the integrative analysis can create a list of well-focused genes as well as to show the correlation between epigenetic changes and gene expression. These gene signatures can help us understand the epigenetic regulation of gene expression and could be potential targets for therapeutic intervention in the future.

Matched MeSH terms: DNA Methylation/genetics*
Fulltext Epigenetic Distribution of Recombinant Plant Chromosome Fragments in a Human-Arabidopsis Hybrid Cell Line

Liaw Y, Liu Y, Teo C, Cápal P, Wada N, Fukui K, et al.

Int J Mol Sci, 2021 May 21;22(11).
PMID: 34063996 DOI: 10.3390/ijms22115426

Methylation systems have been conserved during the divergence of plants and animals, although they are regulated by different pathways and enzymes. However, studies on the interactions of the epigenomes among evolutionarily distant organisms are lacking. To address this, we studied the epigenetic modification and gene expression of plant chromosome fragments (~30 Mb) in a human-Arabidopsis hybrid cell line. The whole-genome bisulfite sequencing results demonstrated that recombinant Arabidopsis DNA could retain its plant CG methylation levels even without functional plant methyltransferases, indicating that plant DNA methylation states can be maintained even in a different genomic background. The differential methylation analysis showed that the Arabidopsis DNA was undermethylated in the centromeric region and repetitive elements. Several Arabidopsis genes were still expressed, whereas the expression patterns were not related to the gene function. We concluded that the plant DNA did not maintain the original plant epigenomic landscapes and was under the control of the human genome. This study showed how two diverging genomes can coexist and provided insights into epigenetic modifications and their impact on the regulation of gene expressions between plant and animal genomes.

Matched MeSH terms: DNA Methylation/genetics
Fulltext Epigenetic Control of the Vasopressin Promoter Explains Physiological Ability to Regulate Vasopressin Transcription in Dehydration and Salt Loading States in the Rat

Greenwood MP, Greenwood M, Gillard BT, Loh SY, Paton JF, Murphy D

J Neuroendocrinol, 2016 04;28(4).
PMID: 26833868 DOI: 10.1111/jne.12371

The synthesis of arginine vasopressin (AVP) in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus is sensitive to increased plasma osmolality and a decreased blood volume, and thus is robustly increased by both dehydration (increased plasma osmolality and decreased blood volume) and salt loading (increased plasma osmolality). Both stimuli result in functional remodelling of the SON and PVN, a process referred to as functional-related plasticity. Such plastic changes in the brain have recently been associated with altered patterns of DNA methylation at CpG (cytosine-phosphate-guanine) residues, a process considered to be important for the regulation of gene transcription. In this regard, the proximal Avp promoter contains a number of CpG sites and is recognised as one of four CpG islands for the Avp gene, suggesting that methylation may be regulating Avp transcription. In the present study, we show that, in an immortalised hypothalamic cell line 4B, the proximal Avp promoter is highly methylated, and treatment of these cells with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine to demethylate DNA dramatically increases basal and stimulated Avp biosynthesis. We report no changes in the expression of DNA methyltransferases, Dnmt1 and Dnmt3a, whereas there is decreased expression of the demethylating enzyme ten-eleven-translocation 2, Tet2, in the SON by dehydration and salt loading. We found higher methylation of the SON Avp promoter in dehydrated but not salt-loaded rats. By analysis of individual CpG sites, we observed hypomethylation, hypermethylation and no change in methylation of specific CpGs in the SON Avp promoter of the dehydrated rat. Using reporter gene assays, we show that mutation of individual CpGs can result in altered Avp promoter activity. We propose that methylation of the SON Avp promoter is necessary to co-ordinate the duel inputs of increased plasma osmolality and decreased blood volume on Avp transcription in the chronically dehydrated rat.

Matched MeSH terms: DNA Methylation/genetics*
Early-life stress changes expression of GnRH and kisspeptin genes and DNA methylation of GnRH3 promoter in the adult zebrafish brain

Khor YM, Soga T, Parhar IS

Gen Comp Endocrinol, 2016 Feb 1;227:84-93.
PMID: 26686318 DOI: 10.1016/j.ygcen.2015.12.004

Early-life stress can cause long-term effects in the adulthood such as alterations in behaviour, brain functions and reproduction. DNA methylation is a mechanism of epigenetic change caused by early-life stress. Dexamethasone (DEX) was administered to zebrafish larvae to study its effect on reproductive dysfunction. The level of GnRH2, GnRH3, Kiss1 and Kiss2 mRNAs were measured between different doses of DEX treatment groups in adult zebrafish. Kiss1 and GnRH2 expression were increased in the 200mg/L DEX treated while Kiss2 and GnRH3 mRNA levels were up-regulated in the 2mg/L DEX-treated zebrafish. The up-regulation may be related to programming effect of DEX in the zebrafish larvae, causing overcompensation mechanism to increase the mRNA levels. Furthermore, DEX treatment caused negative impact on the development and maturation of the testes, in particular spermatogenesis. Therefore, immature gonadal development may cause positive feedback by increasing GnRH and Kiss. This indicates that DEX can alter the regulation of GnRH2, GnRH3, Kiss1 and Kiss2 in adult zebrafish, which affects maturation of gonads. Computer analysis of 1.5 kb region upstream of the 5' UTR of Kiss1, Kiss2, GnRH2 and GnRH3 promoter showed that there are putative binding sites of glucocorticoid response element and transcription factors involved in stress response. GnRH3 promoter analysed from pre-optic area, ventral telencephalon and ventral olfactory bulb showed higher methylation at CpG residues located on -1410, -1377 and -1355 between control and 2mg/L DEX-treated groups. Hence, early-life DEX treatment can alter methylation of GnRH3 gene promoter, which subsequently affects gene regulation and reproductive functions.

Matched MeSH terms: DNA Methylation*
Fulltext DNA methylation and exposure to ambient air pollution in two prospective cohorts

Plusquin M, Guida F, Polidoro S, Vermeulen R, Raaschou-Nielsen O, Campanella G, et al.

Environ Int, 2017 11;108:127-136.
PMID: 28843141 DOI: 10.1016/j.envint.2017.08.006

Long-term exposure to air pollution has been associated with several adverse health effects including cardiovascular, respiratory diseases and cancers. However, underlying molecular alterations remain to be further investigated. The aim of this study is to investigate the effects of long-term exposure to air pollutants on (a) average DNA methylation at functional regions and, (b) individual differentially methylated CpG sites. An assumption is that omic measurements, including the methylome, are more sensitive to low doses than hard health outcomes. This study included blood-derived DNA methylation (Illumina-HM450 methylation) for 454 Italian and 159 Dutch participants from the European Prospective Investigation into Cancer and Nutrition (EPIC). Long-term air pollution exposure levels, including NO2, NOx, PM2.5, PMcoarse, PM10, PM2.5 absorbance (soot) were estimated using models developed within the ESCAPE project, and back-extrapolated to the time of sampling when possible. We meta-analysed the associations between the air pollutants and global DNA methylation, methylation in functional regions and epigenome-wide methylation. CpG sites found differentially methylated with air pollution were further investigated for functional interpretation in an independent population (EnviroGenoMarkers project), where (N=613) participants had both methylation and gene expression data available. Exposure to NO2 was associated with a significant global somatic hypomethylation (p-value=0.014). Hypomethylation of CpG island's shores and shelves and gene bodies was significantly associated with higher exposures to NO2 and NOx. Meta-analysing the epigenome-wide findings of the 2 cohorts did not show genome-wide significant associations at single CpG site level. However, several significant CpG were found if the analyses were separated by countries. By regressing gene expression levels against methylation levels of the exposure-related CpG sites, we identified several significant CpG-transcript pairs and highlighted 5 enriched pathways for NO2 and 9 for NOx mainly related to the immune system and its regulation. Our findings support results on global hypomethylation associated with air pollution, and suggest that the shores and shelves of CpG islands and gene bodies are mostly affected by higher exposure to NO2 and NOx. Functional differences in the immune system were suggested by transcriptome analyses.

Matched MeSH terms: DNA Methylation/drug effects*
Fulltext A potential epigenetic marker mediating serum folate and vitamin B12 levels contributes to the risk of ischemic stroke

Wei LK, Sutherland H, Au A, Camilleri E, Haupt LM, Gan SH, et al.

Biomed Res Int, 2015;2015:167976.
PMID: 25705649 DOI: 10.1155/2015/167976

Stroke is a multifactorial disease that may be associated with aberrant DNA methylation profiles. We investigated epigenetic dysregulation for the methylenetetrahydrofolate reductase (MTHFR) gene among ischemic stroke patients. Cases and controls were recruited after obtaining signed written informed consents following a screening process against the inclusion/exclusion criteria. Serum vitamin profiles (folate, vitamin B12, and homocysteine) were determined using immunoassays. Methylation profiles for CpGs A and B in the MTHFR gene were determined using a bisulfite-pyrosequencing method. Methylation of MTHFR significantly increased the susceptibility risk for ischemic stroke. In particular, CpG A outperformed CpG B in mediating serum folate and vitamin B12 levels to increase ischemic stroke susceptibility risks by 4.73-fold. However, both CpGs A and B were not associated with serum homocysteine levels or ischemic stroke severity. CpG A is a potential epigenetic marker in mediating serum folate and vitamin B12 to contribute to ischemic stroke.

Matched MeSH terms: DNA Methylation/genetics

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